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Valproic Acid

Valproic Acid

INDICATIONS AND DOSE

Treatment of Manic Episodes Associated with Bipolar Disorder

  • By Mouth
    • Adult: Initially 750 mg daily in 2–3 divided doses, then increased to 1–2 g daily, adjusted according to response. Doses greater than 45 mg/kg daily require careful monitoring.

Migraine Prophylaxis

  • By Mouth
    • Adult: Initially 250 mg twice daily, then increased if necessary to 1 g daily in divided doses.

Dose Equivalence and Conversion

  • Semisodium Valproate: Comprises equimolar amounts of sodium valproate and valproic acid.

CONVULEX®

Epilepsy

  • By Mouth
    • Adult: Initially 600 mg daily in 2–4 divided doses, increased in steps of 150–300 mg every 3 days. Usual maintenance 1–2 g daily in 2–4 divided doses, max. 2.5 g daily in 2–4 divided doses.
    • Dose Equivalence and Conversion: Convulex® has a 1:1 dose relationship with products containing sodium valproate, but care is needed if switching or making changes.

Unlicensed Use

  • Not licensed for migraine prophylaxis.

IMPORTANT SAFETY INFORMATION

MHRA/CHM Advice:

  • Antiepileptics: Risk of suicidal thoughts and behavior (August 2008). See Epilepsy p. 333.
  • Antiepileptic Drugs: Updated advice on switching between different manufacturers’ products (November 2017). See Epilepsy p. 333 and also prescribing and dispensing information.
  • Valproate Medicines: Contra-indicated in women and girls of childbearing potential unless conditions of Pregnancy Prevention Programme are met (April 2018).

Valproate is highly teratogenic. Use in pregnancy can lead to neurodevelopmental disorders (approx. 30–40% risk) and congenital malformations (approx. 10% risk). Valproate must not be used in women and girls of childbearing potential unless the conditions of the Pregnancy Prevention Programme are met, and only if other treatments are ineffective or not tolerated as judged by an experienced specialist.

  • MHRA/CHM Advice (December 2018): Ensure compliance with Pregnancy Prevention Programme. Healthcare professionals must continue to identify and review all female patients on valproate and provide them with patient information materials every time they attend appointments or receive their medicines.
  • MHRA/CHM Advice (April 2019): Updated annual risk acknowledgment form and clinical guidance to support compliance with Pregnancy Prevention Programme.

CONTRA-INDICATIONS

  • Acute porphyrias.
  • Known or suspected mitochondrial disorders.
  • Personal or family history of severe hepatic dysfunction.
  • Urea cycle disorders.

CAUTIONS

  • Systemic lupus erythematosus.
  • Liver toxicity: Liver dysfunction (including fatal hepatic failure) has occurred, especially in children under 3 years, usually in first 6 months and involving multiple antiepileptic therapy. Monitor liver function, discontinue if abnormalities persist.

SIDE-EFFECTS

  • Common: Abdominal pain, increased alertness, alopecia (regrowth may be curly), anaemia, abnormal behavior, bone disorders, bone fracture, cerebral atrophy, coma, confusion, impaired consciousness, dementia, diarrhea, diplopia, drowsiness, encephalopathy, fine postural tremor, gastrointestinal disorder, gynecomastia, hemorrhage, hallucination, hearing loss, hepatic disorders, hirsutism, hyperammonaemia, leucopenia, menstrual cycle irregularities, movement disorders, nail

disorder, nausea, obesity, pancreatitis, pancytopenia, parkinsonism, peripheral edema, seizure, severe cutaneous adverse reactions (SCARs), skin reactions, suicidal behaviors, thrombocytopenia, urine abnormalities, vasculitis, vomiting, weight increase.

  • Further Information on Side-Effects: Withdraw treatment immediately if persistent vomiting, abdominal pain, anorexia, jaundice, edema, malaise, drowsiness, or loss of seizure control occurs.

Pancreatitis

  • Discontinue treatment if symptoms develop.

CONCEPTION AND CONTRACEPTION

  • All women and girls of childbearing potential being treated with valproate medicines must be supported on a Pregnancy Prevention Programme. Pregnancy should be excluded before treatment initiation, and highly effective contraception must be used during treatment.

PREGNANCY

  • For migraine prophylaxis [unlicensed] and bipolar disorder: Valproate must not be used.
  • For epilepsy: Valproate must not be used unless there is no suitable alternative treatment. Counseling about the risks should be provided, and a Risk Acknowledgement Form must be signed by both the specialist and the patient. The lowest effective dose should be prescribed in divided doses to avoid peaks in plasma-valproate concentrations. Doses greater than 1 g daily are associated with an increased risk of teratogenicity. Neonatal bleeding (related to hypofibrinaemia) and neonatal hepatotoxicity have been reported. Specialist prenatal monitoring should be instigated when valproate has been taken in pregnancy.

BREASTFEEDING

  • Present in milk—risk of hematological disorders in breast-fed newborns and infants.

HEPATIC IMPAIRMENT

  • Manufacturer advises avoidance.

RENAL IMPAIRMENT

  • Consider dose reduction.

MONITORING REQUIREMENTS

  • Monitor closely if dose greater than 45 mg/kg daily.
  • Monitor liver function before therapy and during the first 6 months, especially in patients most at risk.
  • Measure full blood count and ensure no undue potential for bleeding before starting and before surgery.

EFFECT ON LABORATORY TESTS

  • False-positive urine tests for ketones.

TREATMENT CESSATION

  • In bipolar disorder, avoid abrupt withdrawal; if treatment with valproate is stopped, reduce the dose gradually over at least 4 weeks.

PRESCRIBING AND DISPENSING INFORMATION

  • The Pregnancy Prevention Programme is supported by materials provided by the manufacturer: Patient Guide, Guide for Healthcare Professionals, Risk Acknowledgement Form, and for pharmacists, Patient Cards and Stickers with warning symbols. The MHRA has also produced a patient information sheet providing advice for women and girls taking valproate medicines. The Royal Pharmaceutical Society has also produced a safe supply algorithm available at: www.rpharms.com/safesupplyvalproate.
  • CONVULEX®: Patients being treated for epilepsy may need to be maintained on a specific manufacturer’s branded or generic oral valproic acid product.

PATIENT AND CARER ADVICE

  • Valproate Use by Women and Girls: The MHRA advises that women and girls should not stop taking valproate without first discussing it with their doctor.
  • Blood or Hepatic Disorders: Patients or their carers should be told how to recognize signs and symptoms of blood or liver disorders and advised to seek immediate medical attention if symptoms develop.
  • Pancreatitis: Patients or their carers should be told how to recognize signs and symptoms of pancreatitis and advised to seek immediate medical attention if symptoms such as abdominal pain, nausea, or vomiting develop.
  • Pregnancy Prevention Programme: Pharmacists must ensure that female patients have a patient card.

MEDICINAL FORMS

  • There can be variations in the licensing of different medicines containing the same drug. Forms available from special-order manufacturers include oral suspension and oral solution.

Gastro-resistant Capsule

    • Valproic Acid (Non-proprietary):
      • Valproic Acid (as Valproate Semisodium):
        • 125 mg Depakote 125 mg sprinkle gastro-resistant capsules | 100 capsules P
        • Convulex (Gerot Lannach UK Ltd):
          • Valproic acid 150 mg Convulex 150 mg gastro-resistant capsules | 30 capsules P
          • Valproic acid 300 mg Convulex 300 mg gastro-resistant capsules | 30 capsules P
          • Valproic acid 500 mg Convulex 500 mg gastro-resistant capsules | 30 capsules P

Gastro-resistant Tablet

      • Belvo (Consilient Health Ltd):
        • Valproic acid (as Valproate semisodium) 250 mg Belvo 250 mg gastro-resistant tablets | 30 tablets P
        • Valproic acid (as Valproate semisodium) 500 mg Belvo 500 mg gastro-resistant tablets | 30 tablets P
      • Depakote (Sanofi):
        • Valproic acid (as Valproate semisodium) 250 mg Depakote 250 mg gastro-resistant tablets | 30 tablets P
        • Valproic acid (as Valproate semisodium) 500 mg Depakote 500 mg gastro-resistant tablets | 30 tablets P
      • Syonell (Lupin Healthcare (UK) Ltd):
        • Valproic acid (as Valproate semisodium) 250 mg Syonell 250 mg gastro-resistant tablets | 30 tablets P
  • Valproic acid (as Valproate semisodium) 500 mg Syonell 500 mg gastro-resistant tablets | 30 tablets P

 

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